biostudies-literatureLavalle SNNICHD NIH HHSNIDDK NIH HHSNIEHS NIH HHSNCI NIH HHSNIGMS NIH HHS111577https://www.ebi.ac.uk/biostudies/studies/S-EPMC8934285biostudies-literatureUnknown546The homeodomain transcription factor SIX3 is a known regulator of eye, nose, and forebrain development, and has recently been implicated in female reproduction. Germline heterozygosity of SIX3 is sufficient to cause subfertility, but the cell populations that mediate this role are unknown. The neuropeptide kisspeptin is a critical component of the reproductive axis and plays roles in sexual maturation, ovulation, and the maintenance of gonadotropin secretion. We used Cre-Lox technology to remove Six3 specifically from kisspeptin neurons in mice to test the hypothesis that SIX3 in kisspeptin neurons is required for reproduction. We found that loss of Six3 in kisspeptin neurons causes subfertility and estrous cycle irregularities in females, but no effect in males. Overall, we find that SIX3 expression in kisspeptin neurons is an important contributor to female fertility.Molecular and cellular endocrinologyDeletion of the homeodomain gene Six3 from kisspeptin neurons causes subfertility in female mice.PMC8934285R24 HD102061R01 HD082567T32 HD007203R01 DK044838P50 HD012303F32 HD090837T32 GM008666P42 ES010337P30 CA023100P30 DK063491P50 HD028934R01 HD100580R01 HD072754Naing NCPMellon PLHernandez JLavalle SNHe MYChou TTonsfeldt KJfalseDeletion of the homeodomain gene Six3 from kisspeptin neurons causes subfertility in female mice.The homeodomain transcription factor SIX3 is a known regulator of eye, nose, and forebrain development, and has recently been implicated in female reproduction. Germline heterozygosity of SIX3 is sufficient to cause subfertility, but the cell populations that mediate this role are unknown. The neuropeptide kisspeptin is a critical component of the reproductive axis and plays roles in sexual maturation, ovulation, and the maintenance of gonadotropin secretion. We used Cre-Lox technology to remove Six3 specifically from kisspeptin neurons in mice to test the hypothesis that SIX3 in kisspeptin neurons is required for reproduction. We found that loss of Six3 in kisspeptin neurons causes subfertility and estrous cycle irregularities in females, but no effect in males. Overall, we find that SIX3 expression in kisspeptin neurons is an important contributor to female fertility.2022-01-01T00:00:00Z2022 Apr2025-04-05T11:23:59.623Z2025-04-05T11:23:59.623ZS-EPMC89342853512107610.1016/j.mce.2022.111577